Glioblastoma multiforme (GBM) is the most common and most aggressive human brain tumor. However, despite decades of basic science and clinical research, there is no quick, widely used prognostic criterion for GBM patients (except for non-molecular parameters, such as age; lower survival is correlated with older age) and the outcome for GBM patients remains dismal, with an average survival duration of only 15 months. Thus, new innovative, mechanism-based approaches are necessary for the management of patients with GBM. We have discovered a new regulatory axis based on a novel miR-21-Sox2 axis in GBM patients and patient glioblastoma-derived stem cells through bioinformatic and biochemical studies. This axis appears to classify GBM patients into distinct classes. Based on these results, here we propose to prove or disprove the novel central hypothesis that our GBM classification based on the miR-21-Sox2 axis can produce new prognostic approaches for GBM patients and that this mechanism can also be utilized to develop more effective, less toxic personalized treatment regimens for GBM patient care PUBLIC HEALTH RELEVANCE: The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 15 months and there is no effective therapy. If the Specific Aims of this grant application are completed, not only we wil have the understanding of a new mechanistic axis of GBM tumorigenesis, but this information will also have potentially novel and unconventional translational impact in terms of detection, predict patient outcome and design more effective therapeutic approaches than what is currently used.